The present invention relates to the lyophilization of cyclophosphamide.
U.S. Pat. No. 4,537,883 to Alexander et al. (Mead Johnson & Co.) discloses various lyophilizates of cyclophosphamide. These lyophilizates are prepared by lyophilizing a solution of cyclophosphamide and one or more excipients and re-hydrating the product such that it contains about 4% moisture. The patent is based upon a comparative study of lyophilizate cakes and the dissolution time for lyophilizates of cyclophosphamide prepared using a number of excipients. The study concludes that the lyophilizate prepared with mannitol gives a better cake and faster dissolution time than the lyophilizates prepared with other excipients. The patent also teaches that the lyophilized cyclophosphamide-mannitol composition exhibits better thermal stability if it contains an equimolar amount of water based on cyclophosphamide. The preferred lyophilizate contains 20 parts cyclophosphamide, 1.25 to 2 parts water and 10 to 85 parts mannitol. Among the excipients evaluated in the patent are mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid.
In lyophilizing cyclophosphamide, it is known that cyclophosphamide monohydrate is more stable than anhydrous cyclophosphamide. As a result, a practice has developed wherein in preparing lyophilized pharmaceutical preparations containing cyclophosphamide, the bound water or water of crystallization is removed from the cyclophosphamide in the lyophilizer and a small amount of water is back added to the composition to convert the less stable anhydrous cyclophosphamide product to the more stable monohydrate. This practice is described in U.S. Pat. No. 4,537,883 to Alexander and in T.R. Kovalcik and J.K. Guillory "The Stability of Cyclophosphamide in Lyophilized Cakes," J. Paren. Sci. & Tech., 42, No. 1, p. 29-37 (1988). It is also described in commonly assigned U.S. applications 07/597,965 and 07/583,896.
The process of back adding water is not satisfactory when using certain bulking agents, such as lactose, which take up the water which is back added to the composition. Such bulking agents compete with the cyclophosphamide for the water. Because these bulking agents have a higher affinity for water than cyclophosphamide, the cyclophosphamide may never be converted to the monohydrate as desired.
Published European Application 0 401 894 to Pharmachemie discloses a lyophilization process for preparing freeze-dried cyclophosphamide monohydrate without any bulking agent. Cyclophosphamide monohydrate is commercially available neat, i.e., without any bulking agent. This compound might be administered to patients directly but it is difficult to dissolve and hence difficult to reconstitute. Accordingly, it would be desirable to have a more readily dissolvable form of cyclophosphamide monohydrate. While not desiring to be bound, it is believed that lyophilizates in accordance with the invention described below may have a unique crystalline structure which renders them more easy to dissolve and reconstitute.